Computed tomography (CT) is a powerful diagnostic tool based on X-ray attenuation that provides 3D or 4D images with spatial resolutions <1 mm for clinical scanners used for humans and about 15 microns for micro-CT used for small animals. Contrast agents including small-molecule contrast agents are frequently injected into patients undergoing CT scans. The contrast agents improve the visualization of structures such as blood vessels and tumors. However, certain properties of current small-molecule contrast agents are not optimal including non-specific distribution of the contrast agent, rapid clearance of the agent by the kidney and toxicity of the agent. In addition, it is difficult to administer certain contrast agents in higher concentrations which would be useful to improve visualization.
Contrast agents of nanometer-scale dimensions are emerging as powerful probes for in vivo imaging in medical and biological diagnostics (Hahn, M. A., et al., Nanoparticles as Contrast Agents for in-vivo Bioimaging: Current Status and Future Perspectives. Anal Bioanal. Chem. 2011, 399, 3-27). Iodinated organic molecules are the most universally accepted CT contrast agents used clinically. The high atomic number (Z) element in these agents (i.e., iodine) is typically covalently bound, which makes the agents relatively safe for use in humans. Methods to fabricate nano-scale contrast agents (NCAs) of iodinated molecules have focused on incorporating the molecules into nanoparticles using emulsions, liposomes, lipoproteins, and polymers. The methods have been applied in vivo with varying degrees of success. A common drawback of these iodinated NCAs is that it is often necessary to covalently modify a small-molecule contrast agent for incorporation into a nanoparticle. For example, the agent DTA was converted to an ester to be included into a suspension with a surfactant (McIntire, G. L.; et al., Pulmonary Delivery of Nanoparticles of Insoluble, Iodinated CT X-ray Contrast Agents to Lung Draining Lymph Nodes in Dogs. J. Pharm. Sci. 1998, 87, 1466-1470). Iodinated functional groups also often need to be covalently integrated into the backbone of a polymer (de Vries, A.; et al., H. Block-Copolymer-Stabilized Iodinated Emulsions for Use as CT Contrast Agents. Biomater. 2010, 31, 6537-6544). In cases where a covalent modification is not required (e.g., liposome), it can be difficult to achieve a high payload of the contrast agent (Konga, W. H.; et al., Biomater. 2007, 28, 5555-5561). Moreover, in addition to being time consuming and potentially low-yielding, the covalent approach, de facto, affords a molecule that consists of new covalent linkages (Whitesides, G. M.; et al., Molecular Self-Assembly and Nanochemistry: A Chemical Strategy for the Synthesis of Nanostructures. Science 1991, 254, 1312-1319), which can create difficulties when attempting to have the material approved for commercial use and application. Accordingly, there is a need for new compositions (e.g., co-crystals and salts) of contrast agents.